Plants and marine organisms provide a rich source of compounds that have been investigated and exploited for a variety of medicinal and biological applications. The Euphorbiaceae family is one of the largest families of plants with about 300 genera and 7,500 species, mostly monoecious herbs, shrubs and trees, sometimes succulent and cactus-like, that are further frequently characterized by a milky sap or latex material. Members of the Euphorbiaceae family have been investigated as providing potential treatments for cancers, tumors and warts. Active components found in members of this plant family may be common to several genera or species of the family or may be limited to a particular genus or species.
Certain Euphorbiaceae species have been shown to synthesize phorbol ester and diterpene diester compounds having therapeutic effects on certain cancers. For instance, the isolation and characterization of antileukemic properties from Euphorbia esula L and Croton tiglium L. have been reported. S. M. Kupchan et al., Science 191: 571-572 (1976). The fractionation of an active extract led to the characterization of the antileukemic component from Euphorbia esula L as a diterpene diester. Fractionation of croton oil led to the characterization of the active component known as a phorbol diester, phorbol 12-tiglate 13-decanoate.
One of the most investigated phorbol ester derived from certain members of the Euphorbiaceae family is TPA, 12-O-tetradecanoyl-13-phorbol acetate. Although TPA is primarily recognized as a tumor promoter when topically applied to the skin of mice, the compound was also found to stimulate differentiation and inhibit DNA synthesis of HL-60 human promyelocytic leukemia cells in vitro. The effect of this compound when administered to human patients with myeloid malignancies was also examined. Intravenous dosages of 1 mg of TPA was shown to have pharmacological activity for the treatment of myelocytic leukemia in patients refractory to cytosine arabinoside, retinoic acid and other antileukemic drugs. Han et al. Proc. Nat'l Acad. Sci. 95; 5357-5361 (1998). Likewise, the intravenous administration of TPA in human patients having low white blood cell (WBC) counts due to prior treatments of solid tumors with a cytotoxic chemotherapuetic agent, caused an increase in WBC count and neutrophilia in the blood. Han et al. Proc. Nat'l Acad. Sci. 95; 5362-5365 (1998).
However, the administration of TPA, even at relatively small doses of 0.5 to 1 mg appeared to have toxic effects in vivo. Moreover, the therapeutic effects appear to be limited to a particular cell type or particular mode of administration. Further, no distinction was made in the references to whether TPA, and any other active component derived from plants from the Euphorbiaceae family, was obtained from the outer cortex or latex material of the plant.
The phorbol esters derived from other Euphorbiaceae species that are examined in these references have different physical and chemical properties as compared to the extract of the present invention, which is derived from the Euphorbia obesa (hereinafter, “EO”) species. For instance, when compared to TPA by thin layer chromatography (TLC) analysis, the EO extract of the present invention has different mobilities. In addition, the absorption max and visible color of the EO extract and TPA are distinct. EO is a succulent, thornless, cactus-like plant that grows in temperate climates and is typically used in gardens for their ornamental value. Due to its ribbing or stitch-like ridges, the plant is commonly referred to as “the baseball plant.” No biological or medicinal properties have been identified from this particular species. Thus, there is a need to isolate and evaluate novel compounds having anti-tumor activity from the EO species of the Euphorbiaceae family.